Quinolone compounds are known primarily as antibacterial agents (see JP-A-05025162; U.S. Pat. No. 5037834; EP-A-0420069; WO-A-9410163; JP-A-02040379; EP-A-0343560; U.S. Pat. No. DE 3816119; EP-A-0304158; and U.S. Pat. No. DE 3641312) or antiviral agents (U.S. Pat. No. 4,959,363) but also as inhibitors of 5-lipoxygenase (JP-A-02124871), cardiotonics and vasodilators (JP-A-01061461) and 5-HT.sub.3 antagonists for the treatment of peripheral disorders associated with pain (WO-A-9501793 and GB-A-2236751). None of these publications discloses utility as PDE IV inhibitors.
Phosphodiesterases regulate cyclic AMP/GMP concentrations. Phosphodiesterase IV (PDE IV) has been demonstrated to be a principal regulator of cyclic AMP in respiratory smooth muscle and inflammatory cells see Torphy and Cieslinski, Molecular Pharmacology 37:206 (1990); Dent et al, British Journal of Pharmacology, 90:163p (1990)!. Inhibitors of phosphodiesterase IV have been implicated as being bronchodilators and asthma-prophylactic agents, as agents for inhibiting eosinophil accumulation and the function of eosinophils see for example Gembycz and Dent, Clinical and Experimental Allergy 22:337 (1992)! and for treating other diseases and conditions characterised by, or having an etiology including, morbid eosinophil accumulation. Inhibitors of PDE IV are also implicated in treating inflammatory diseases, proliferative skin disease and conditions associated with cerebral metabolic inhibition.
Tumour Necrosis Factor (TNF) is a serum glycoprotein. Excessive or unregulated TNF production has been implicated in mediating or exacerbating a number of diseases including rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritic conditions; sepsis, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, adult respiratory distress syndrome, cerebral malaria, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcoidosis, bone resorption diseases, reperfusion injury, graft vs. host reaction, allograft rejections, fever and myalgias due to infection, such as influenza, cachexia secondary to infection or malignancy, cachexia secondary to human acquired immune deficiency syndrome (AIDS), AIDS, ARC (AIDS-related complex), keloid formation, scar tissue formation, Crohn's disease, ulcerative colitis, or pyresis, in addition to a number of autoimmune diseases, such as multiple sclerosis, autoimmune diabetes and systemic lupus erythematosis.
AIDS results from the infection of T lymphocytes with Human Immunodeficiency Virus (HIV). At least three types or strains of HIV have been identified, i.e., HIV-1, HIV-2 and HIV-3. As a consequence of HIV infection, T-cell mediated immunity is impaired and infected individuals manifest severe opportunistic infections and/or unusual neoplasms. HIV entry into the T lymphocyte requires T lymphocyte activation. Viruses such as HIV-1 or HIV-2 infect T lymphocytes after T cell activation and such virus protein expression and/or replication is mediated or maintained by such T cell activation. Once an activated T lymphocyte is infected with HIV, the T lymphocyte must continue to be maintained in an activated state to permit HIV gene expression and/or HIV replication.
Cytokines, specifically TNF, are implicated in activated T-cell mediated HIV protein expression and/or virus replication by playing a role in maintaining T lymphocyte activation. Therefore, interference with cytokine activity such as by inhibition of cytokine production, notably TNF, in an HIV-infected individual aids in limiting the maintenance of T cell activation, thereby reducing the progression of HIV infectivity to previously uninfected cells which results in a slowing or elimination of the progression of immune dysfunction caused by HIV infection. Monocytes, macrophages, and related cells, such as Kupffer and glial cells, have also been implicated in maintenance of the HIV infection. These cells, like T cells, are targets for viral replication and the level of viral replication is dependent upon the activation state of the cells see Rosenberg et al, The Inmunopathogenesis of HIV Infection, Advances in Immunology, Vol. 57, (1989)!. Monokines, such as TNF, have been shown to activate HIV replication in monocytes and/or macrophages See Poli et al, Proc. Natl. Acad. Sci., 87:782-784 (1990)!. Therefore, inhibition of monokine production or activity aids in limiting HIV progression as stated above for T cells.
TNF has also been implicated in various roles with other viral infections, such as the cytomegalovirus (CMV), influenza virus, adenovirus, and the herpes virus for similar reasons as those noted.
TNF is also associated with yeast and fungal infections. Specifically, Candida albicans has been shown to induce TNF production in vitro in human monocytes and natural killer cells. See Riipi et al, Infection and Immunity, 58(9):2750-54 (1990); and Jafari et al, Journal of Infectious Diseases, 164:389-95 (1991). See also Wasan et al, Antimicrobial Agents and Chemotherapy, 35(10):2046-48, (1991); and Luke et al, Journal of Infectious Diseases, 162:211-214, (1990)!.
The ability to control the adverse effects of TNF is furthered by the use of the compounds which inhibit TNF in mammals who are in need of such use. There remains a need for compounds which are useful in treating TNF-mediated disease states which are exacerbated or caused by the excessive and/or unregulated production of TNF.
U.S. Pat. No. 4,786,644 discloses a variety of compounds including what may be quinolone-3-carboxamides. There is also an aryl substituent at the 1-position.
U.S. Pat. No. 4,621,088 discloses 1-ethylquinolone-3-carboxamides, and heterocyclic analogues, having an acyl substituent on the carboxamide group; the acyl substituent may be cyclohexylmethyl carrying a COOH group. These compounds are disclosed as having an antiallergic action.
U.S. Pat. No. 3,524,858 and GB-A-1191443 disclose, inter alia, 1-alkylquinolone-3-carboxamides having an aryl or aralkyl substituent on the carboxamide group. These compounds are disclosed as having anti-viral activity.
Other quinolone-3-carboxamides are known, in which there is an optionally-substituted phenyl substituent on the carboxamide group. None of these disclosures mentions utility as PDE IV inhibitors.